Pharmaceutical compounds

ABSTRACT

Compounds of formula (I), wherein E, G, T, R d , R e , and R f  are as defined in the disclosure, release levodopa and a COMT inhibitor so that they can be used for the treatment of diseases or conditions, wherein levodopa and inhibition of COMT are indicated to be useful.

FIELD OF THE INVENTION

The present invention relates to codrugs of unprotected or suitablyprotected levodopa and a catechol O-methyltransferase (COMT) inhibitor,or pharmaceutically acceptable salts or esters thereof. The inventionfurther relates to pharmaceutical compositions thereof.

BRIEF DESCRIPTION OF THE PRIOR ART

The prodrug approach is commonly used to improve physicochemical,biopharmaceutical, and drug delivery properties of therapeutic agents.Ideally, an inactive pro-moiety is attached by covalent bonding to theparent molecule, and the resulting prodrug is converted to the parentdrug in the body before it exhibits its pharmacological effect. Manydiseases are treated by a combination of therapeutic agents that areco-administered in separate dosage forms.

However, there are potential advantages, e.g. improved deliveryproperties and targeting drugs to specific sites of action, in givingthe co-administered agents as a single chemical entity. In codrugs, atleast two synergistic drugs are linked together and designed to releasethe parent drug at the desired site of action.

Levodopa (3,4-dihydroxyphenyl-L-alanine) is a precursor to dopamine,which is deficient in the brains of patients suffering from Parkinson'sdisease (PD). Conventional PD treatment consists of levodopa combinedwith an amino acid decarboxylase (MDC) inhibitor, such as carbidopa.During treatment, COMT remains the main enzyme for metabolizinglevodopa. Entacapone[(E)2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide] is anew, potent inhibitor of COMT. Entacapone is currently used as aclinical adjunct to levodopa therapy in PD treatment. The administrationof entacapone, together with levodopa and an MDC inhibitor, leads toincreased bioavailability of levodopa and its prolonged duration ofaction. However, even after combination therapy of entacapone andlevodopa, the bioavailability of levodopa is low, i.e. 5-10% [Männistöet al. Pharmacol Toxicol., 66 (1990) 317]. In addition, thebioavailability of entacapone after oral administration is also low,i.e. 29-46% [Keranen et al. Eur. J. Clin. Pharmacol., 46 (1994) 151].

The codrug approach can be considered to be a productive way forcombining the therapeutic effects of levodopa and a COMT inhibitor. Aneffective codrug is stable against chemical hydrolysis, but releases theparent drugs e.g. by enzymatic hydrolysis under physiologicalconditions.

SUMMARY OF THE INVENTION

The object of the present invention is to provide compounds that releaselevodopa and a COMT inhibitor.

The invention also provides compounds for the treatment of diseases orconditions, wherein levodopa and inhibition of COMT are indicated to beuseful, as well as a use thereof for the manufacture of a medicament tobe used as a precursor for levodopa and a COMT inhibitor. Furthermore,pharmaceutical compositions containing the present compounds areprovided.

DETAILED DESCRIPTION OF THE INVENTION

Levodopa can be linked to the COMT inhibitor via a spacer. Preferably,the COMT inhibitor is a derivative of a catechol compound. Suitablecatechol COMT inhibitors for the use of the invention are disclosed e.g.in the following publications: GB 2 200 109 A; U.S. Pat. No. 6,150,412;EP 237 929 B1; and EP 1 010 688 A1.

The present invention thus provides compounds of general formula I,

wherein E is a COMT inhibitor moiety; G is —(CO)_(a)—, wherein a is 0 or1; T is —(CH₂)_(b)—, wherein b is depending on a

-   -   if a is 0, then b is 0    -   if a is 1, then b is 2 or3    -   R_(d) and R_(e) independently are hydrogen or groups        hydrolyzable under physiological conditions, and signify        optionally substituted lower alkanoyl or aroyl, lower        alkanoylamino, optionally substituted lower alkyl or        arylsulphonyl or optionally substituted lower alkylcarbamoyl, or        taken together signify a lower alkylidene or cycloalkylidene        group; R_(f) is hydrogen or a group hydrolyzable under        physiological conditions, and signifies optionally substituted        lower alkanoyl or aroyl, lower alkylamino or lower dialkylamino        or lower alkanoylamino, optionally substituted lower alkyl or        arylsulphonyl or optionally substituted lower alkylcarbamoyl, or        pharmaceutically acceptable esters or salts thereof. Preferably,        R_(f) is hydrogen or alkyl, e.g. alkyl. Further preferably,        R_(d) and R_(e) independently are hydrogen or optionally        substituted alkanoyl or aroyl. Compounds, wherein E is a        derivative of a catechol compound, are preferred. In the        definitions of R_(d), R_(e), and R_(f), the term “lower” denotes        residues with a maximum of 8, preferentially a maximum of 4        carbon atoms. The term “alkyl” taken alone or in combination        with terms such as “alkanoyl, alkylidene, cycloalkylidene,        alkylamino” denotes straight or branched chain saturated or        partially unsaturated hydrocarbon residues. The term “aryl” in        combination with terms such as “aroyl” denotes a carbocyclic        aromatic group, preferably mono- or bicyclic groups. The term        “optionally substituted” in connection with various residues        refers to halogen substituents, such as fluorine, chlorine,        bromine, iodine or trifluoromethyl groups, alkyloxy, or aryl        substituents. The “optionally substituted” groups may contain 1        to 3, preferably 1 or 2, most preferably 1 of said substituents.

Compounds of formula I provide adequate stability against chemicalhydrolysis at acidic pH, which is a desirable property considering theconditions in the stomach and small intestine, and, additionally, showappropriate biodegradability.

As a subgroup of the compounds of formula 1, the invention providescompounds, wherein E is a catechol COMT inhibitor as disclosed in GB 2200 109 A, i.e. E is a moiety of formula Ia,

wherein R₂ is hydrogen, optionally substituted acyl or aroyl, loweralkylsulfonyl or alkylcarbamoyl, X comprises an electronegativesubstituent such as halogen, nitro, cyano, lower alkylsulfonyl,sulfonamido, aldehyde, carboxyl or trifluoromethyl; R₃ is hydrogen,halogen, substituted alkyl, hydroxyalkyl, amino, nitro, cyano,trifluoromethyl, lower alkylsulfonyl, sulfonamido, aldehyde, alkylcarbonyl, aralkylidene carbonyl or carboxyl or a group selected from

-   -   —CH═CR₄R₅ and —CH₂CHR₄R₅, wherein R₄ is hydrogen, alkyl, amino,        cyano, carboxyl or acyl; and R₅ is hydrogen, amino, cyano,        carboxyl, alkoxycarbonyl, carboxy alkenyl, nitro, acyl,        hydroxyalkyl, carboxyalkyl or an optionally substituted        carboxamido, carbamoyl or aroyl or heteroaroyl, or R₄ and R₅        together form a five to seven membered substituted cycloalkanone        ring;    -   —(CO)_(n)(CH₂)_(m)—COR, wherein n is 0 or 1 and m is 0 or 1-7        and R is hydroxy, alkyl, carboxyalkyl, optionally substituted        alkene, alkoxy or optionally substituted amino;    -   —CONR₈R₉, wherein R₈ and R₉ independently are hydrogen or one of        the following optionally substituted groups; alkyl, alkenyl,        alkynyl, cycloalkyl, aralkyl, or together form an optionally        substituted piperidyl group; and —NH—CO—R₁₀, wherein R₁₀ is a        substituted alkyl group. Preferably, R₂ is hydrogen. Further        preferably, X is at ortho position to R₂O—. In the definitions        of R, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, and R₁₀, the term “alkyl”        by itself or as part of another group includes both straight and        branched chain radicals of up to 18 carbon atoms, preferably 1        to 8 carbon atoms, most preferably 1 to 4 carbon atoms. The term        “lower alkyl” by itself or as part of another group includes        both straight and branched chain radicals of 1 to 7, preferably        1 to 4, most preferably 1 or 2 carbon atoms. The terms “alkenyl”        and “alkynyl” designate a hydrocarbon residue as defined above        with respect to the term “alkyl” including at least one carbon        to carbon double bond and carbon to carbon triple bond,        respectively. The alkenyl and alkynyl residues may contain up to        12, preferably 1 to 8, most preferably 1 to 4 carbon atoms. The        term “acyl” by itself or as part of another group refers to an        alkylcarbonyl or alkenylcarbonyl group. The term “aroyl” by        itself or as part of another group refers to an arylcarbonyl        group, the aryl group being a mono- or bicyclic group containing        from 6 to 10 carbon atoms in the ring portion. Specific examples        for aryl groups are phenyl, naphthyl, and the like. The term        “lower alkylidene” refers to a chain containing from 2 to 8,        preferably 2 to 4 carbon atoms. The term “alkoxy” by itself or        as part of another group includes an alkyl residue linked to an        oxygen atom. The term “cycloalkyl” includes saturated cyclic        hydrocarbon groups containing 3 to 8, preferably 5 to 7 carbon        atoms. The term “aralkyl” refers to alkyl groups having an aryl        substituent. A specific example is the benzyl group. The term        “halogen” as refers to chlorine, bromine, fluorine or iodine,        chlorine and bromine being preferred. The term “optionally        substituted” in connection with various residues refers to        halogen substituents, such as fluorine, chlorine, bromine,        iodine or trifluoromethyl groups, alkyloxy, aryl, alkyl-aryl,        halogen-aryl, cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino,        alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, or        alkylthio substituents. The “optionally substituted” groups may        contain 1 to 3, preferably 1 or 2, most preferably 1 of said        substituents. The term “heteroaroyl” refers to mono- or bicyclic        groups containing 1 to 3, preferably 1 or 2 heteroatoms N and/or        O and/or S.

As a further subgroup of the compounds of formula I, the inventionprovides compounds, wherein E is a catechol COMT inhibitor as disclosedin U.S. Pat. No. 6,150,412, i.e. E is a moiety of formula Ib,

wherein R₁ is an electronegative substituent, preferably nitro, cyano,formyl or carboxy; R₂ is -A-R₄, wherein A is branched or straight chain(C₁₋₉)alkylene; R₄ is carboxy, 5-tetrazolyl, R₅ or CO—R₅, wherein R₅ isphenyl or (C₃₋₇)cycloalkyl which is substituted by at least one carboxyor 5-tetrazolyl; R₃ is an electronegative substituent, preferably nitro,cyano, halogen, formyl, carboxy, (C₁₋₅)alkylcarbonyl, arylcarbonyl orSO₂R₆, wherein R₆ is branched or straight chain (C₁₋₅)alkyl, arylalkyl,aryl or NR₇R₈, wherein R₇ and R₈ are independently hydrogen or branchedor straight chain (C₁₋₅)alkyl, or together form a (C₃₋₆)ring, the term“aryl” meaning phenyl or naphthyl.

As a further subgroup of the compounds of formula I, the inventionprovides compounds, wherein E is a catechol COMT inhibitor as disclosedin EP 237 929 B1, i.e. E is a moiety of formula Ic,

-   -   wherein R_(a) is nitro or cyano; R_(b) is hydrogen or halogen,        R_(c) is halogen, nitro, cyano or a group -(A)_(n)-(Q)_(m)-R¹ or        -(A)_(n)-Q-R², A is vinylene optionally substituted by lower        alkyl, n is 0 or 1, m is 0 or 1, R is —COR^(3,) an aromatic        carbocyclic group or an aromatic or partially unsaturated        heterocyclic group attached via a carbon atom, R² is hydrogen or        an optionally substituted, saturated or partially unsaturated        lower hydrocarbon residue, R³ is hydroxy, amino, an optionally        substituted, saturated or partially unsaturated lower        hydrocarbon residue attached via an oxygen atom or an imino or        lower alkylimino group or a saturated, N-containing heterocyclic        group attached via a ring nitrogen atom, Q is the group —CO— or        >C═N-(Z)_(p)R⁴, Z is an oxygen atom or an imino group, p is 0 or        1 and R⁴ is hydrogen or a saturated or partially unsaturated,        lower hydrocarbon residue which is optionally substituted and        which is optionally attached via a carbonyl group. In the        definitions of R_(a), R_(b), and R_(c), the term “lower” denotes        residues and compounds with a maximum of 7, preferably a maximum        of 4, carbon atoms. The term “alkyl”, taken alone or in        combinations, such as “alkyl group”, “alkoxy”, “alkylthio”, and        “alkylimino”, denotes straight chain or branched, saturated        hydrocarbon residues, for example, such as methyl, ethyl,        propyl, isopropyl, n-butyl, s-butyl, i-butyl, t-butyl and the        like. The term “saturated or partially unsaturated lower        hydrocarbon residue” denotes open chain and cyclic groups and        combinations thereof. Examples of saturated and partially        unsaturated lower hydrocarbon residues are: lower alkyl groups        such as those defined above: lower alkenyl groups, for example,        2-propenyl, 2-butenyl, 3-butenyl, and 2-methyl-2-propenyl; C₃₋₇        cycloalkyl and C₈₋₁₀ bicycloalkyl groups optionally substituted        by lower alkyl groups, for example, cyclopropyl, cyclopentyl,        2-methylcyclopentyl, cyclohexyl, and 3-methylcyclohexyl; lower        cycloalkenyl groups optionally substituted by lower alkyl        groups, for example, 3-cyclopentenyl, 1-methyl-3-cyclopentenyl,        and 3-cyclohexenyl; lower alkyl or alkenyl groups substituted by        lower cycloalkyl or cycloalkenyl groups, for example,        cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl,        cyclohexylmethyl, 2-cyclohexenylmethyl, and        3-cyclopropyl-2-propenyl. The lower alkenyl groups preferably        contain 2-4 carbon atoms; the cycloalkyl and cycloalkenyl groups        preferably contain 3-6 carbon atoms. The following come into        consideration as substituents for the above lower hydrocarbon        residues: hydroxy, cyano, nitro, halogen, amino, lower        alkylamino, di(lower alkyl)amino, lower alkoxy, lower        alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl,        arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl,        mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy,        trifluoromethyl, carboxy, lower alkanoylamino, lower        alkoxycarbonylamino, and lower alkylthio. The saturated or        partially unsaturated lower hydrocarbon residues are preferably        unsubstituted or mono- or disubstituted. The term “aryl” denotes        carbocyclic aromatic groups, preferably mono- or bicyclic        groups. Especially preferred carbocyclic aromatic groups are        phenyl and naphthyl, especially phenyl. These groups are        optionally substituted by halogen trifluoromethyl, nitro, amino,        mono- or di(lower alkyl)amino, lower alkyl, lower alkoxy, lower        alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy,        hydroxy, cyano, lower alkanoyloxy, carbamoyl, mono- or di(lower        alkyl)carbamoyl, lower alkylenedioxy, lower alkanoylamino or        lower alkoxycarbonylamino. The carbocyclic aromatic groups are        preferably unsubstituted or mono- or disubstituted. The term        “aromatic or partially unsaturated heterocyclic group”        preferably denotes a mono-, di- or tricyclic, aromatic or        partially unsaturated heterocyclic group with up to five        heteroatoms from the group consisting of nitrogen, sulfur, and        oxygen. The heterocyclic groups preferably contain 1-4 nitrogen        atoms and/or an oxygen or sulfur atom. They are preferably mono-        or bicyclic. The heteroatoms are preferably distributed on one        or two rings, whereby nitrogen atoms can simultaneously also be        components of two rings. The heterocyclic groups are preferably        aromatic. They can be substituted and are preferably mono, di-        or trisubstituted. As substituents there come into consideration        halogen, trifluoromethyl, nitro, carboxy, amino, arylamino,        lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower        alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto,        lower alkylthio, lower alkylamino, di(lower alkyl)amino, C₃₋₇        cycloalkylamino, C₈₋₁₀ bicycloalkylamino, lower alkanoylamino,        lower alkoxycarbonylamino, carbamoyl, mono- or di(lower        alkyl)carbamoyl, cyano, aryl, aryl(lower alkyl), aryl(lower        alkyl)amino, heteroaryl, heteroaryl(lower alkyl),        heteroarylamino, and C₃₋₇ cycloalkyl. The monocyclic        heterocyclic groups are preferably five or six membered and        contain a maximum of 4 heteroatoms. The bicyclic heterocyclic        groups are preferably eight to ten membered, with the individual        rings being preferably five or six membered. The following are        to be mentioned as examples of such heterocyclic groups:        pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl,        oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl,        thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl,        benzoxazinyl, quinoxalinyl, benzopyranyl, benzimidazolyl,        indolyl, imidazothiazolyl, imidazothiadiazolyl, imidazopyridyl,        benzothiazinyl, benzoquinoxalinyl, and imidazobenzothiazolyl.        The term “heteroaryl” denotes aromatic heterocyclic groups, as        defined above. The term “saturated, N-containing heterocyclic        group attached via a ring nitrogen atom” preferably denotes a        three to seven membered, preferably four to six membered,        saturated N-heterocycle which, in addition to the said nitrogen        atom, can contain an oxygen, sulfur or nitrogen atom as a second        heteroatom. These saturated N-heterocycles can be mono- or        disubstituted by lower alkyl, hydroxy, lower alkoxy, lower        alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower        alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl,        carbamoyl, mono- or di(lower alkyl)carbamoyl, oxo and/or lower        alkylenedioxy. The following are to be mentioned as examples of        such N-containing heterocyclic groups: 4-morpholinyl,        1-pyrrolidinyl, and 1-azetidinyl.

As a further subgroup of the compounds of formula I, the inventionprovides compounds, wherein E is a catechol COMT inhibitor as disclosedin EP 1 010 688 A1, i.e. E is a moiety of formula Id,

wherein R₂ is hydrogen or a group hydrolyzable under physiologicalconditions, and signifies optionally substituted lower alkanoyl oraroyl, optionally substituted lower alkyl or arylsulphonyl or optionallysubstituted lower alkylcarbamoyl; R₃, R₄, and R₅ are the same ordifferent and signify hydrogen, optionally substituted saturated orpartially unsaturated lower hydrocarbon residue, hydroxy, optionallysubstituted lower alkoxy or aryloxy group, optionally substituted aryl,optionally substituted alkanoyl or aroyl group, lower alkanoylaminogroup, lower dialkanoylamino group, carboxyl, optionally substitutedlower alkyloxycarbonyl or aryloxycarbonyl group, optionally substitutedcarbamoyl, halogen, nitro, amino, lower alkylamino or lower dialkylaminoor cyano group, or taken together signify aliphatic or heteroaliphaticrings or aromatic or heteroaromatic rings. Preferably, R₂ is hydrogen.In the definitions of R₂, R₃, R₄, and R₅, the term “lower” denotesresidues with a maximum of 8, preferentially a maximum of 4 carbonatoms. The term “alkyl” taken alone or in combination with terms such as“alkanoyl, alkyloxycarbonyl, alkylamino” denotes straight or branchedchain saturated hydrocarbon residues. The term halogen denotes fluorine,chlorine, bromine, and iodine. The term “aryl” denotes a carbocyclicaromatic group, preferably mono- or bicyclic groups.

Preferably, the compound is(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester or(S)-3-(3,4-dihydroxyphenyl)-2-[2-hydroxy-5-(4-methylbenzoyl)-3-nitrophenoxycarbonylamino]propionicacid methyl ester, or pharmaceutically acceptable esters or saltsthereof.

Pharmaceutically acceptable salts and esters of all compounds disclosedabove, when applicable, may be prepared by known methods. Thepharmaceutically acceptable salts are the usual organic and inorganicsalts of the art. Such salts are well known in the literature.

The invention provides compounds for the treatment of disorders orconditions wherein levodopa and inhibition of COMT are indicated to beuseful, as well as a use thereof for the manufacture of a medicament tobe used as a precursor for levodopa and a COMT inhibitor. Furthermore,pharmaceutical compositions containing the present compounds areprovided.

The compounds of the invention can be prepared by a variety of syntheticroutes analogously to or according to the methods known in theliterature using suitable starting materials.

In general, compounds of formula I can be prepared e.g. analogously toor according to scheme 1,

wherein R is e.g. alkyl, R′ is e.g. acyl, and E, G, and T are as definedabove.

The carboxylic group of levodopa is protected in a conventional manner,e.g. as an alkyl ester, e.g. as the methyl ester. The hydroxy groups areprotected in a conventional manner, e.g. with acyl protecting groups.The desired spacer between the levodopa and COMT inhibitor moieties isaccomplished by using appropriate reagents and reactions known in thechemical field, and thereafter the COMT inhibitor moiety can be insertedby known methods. This can be achieved e.g. via an isocyanate or via adicarboxylic acid monoamide as shown in the specific examples. Theprotected hydroxy groups can, if desired, be removed in a conventionalmanner.

The synthetic routes described above are meant to illustrate thepreparation of the compounds of the invention and the preparation is byno means limited thereto, i.e. there are also other possible syntheticmethods which are within the general knowledge of a person skilled inthe art.

The compounds of the invention may be converted, if desired, into theirpharmaceutically acceptable salts or esters using methods well known inthe art.

The compounds of the invention may be administered enterally, topicallyor parenterally.

The compounds according to this invention are given to a patient as suchor in combination with one or more other active ingredients and/orsuitable pharmaceutical excipients. The latter group comprisesconventionally used excipients and formulation aids, such as fillers,binders, disintegrating agents, lubricants, solvents, gel formingagents, emulsifiers, stabilizers, colorants and/or preservatives.

The compounds used in this invention are formulated into dosage formsusing commonly known pharmaceutical manufacturing methods. The dosageforms can be e.g. tablets, capsules, granules, suppositories, emulsions,suspensions or solutions. Depending on the route of administration andthe galenic form, the amount of the active ingredient in a formulationcan typically vary between 0.01 and 100% (w/w).

The present invention will be explained in more detail by the followingexamples. The examples are meant for illustrating purposes only and donot limit the scope of the invention defined in the claims.

EXAMPLE 1(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester

Levodopa (2 g, 10 mmol) was treated with thionyl chloride (5 ml) in drymethanol (10 ml). The resulting white solid was stirred withtrifluoroacetic acid (4 ml) and acetyl chloride (1.5 ml) at roomtemperature to give (S)-2-amino-3-(3,4-diacetoxyphenyl)propionic acidmethyl ester with quantitative yield and high purity. The HCl salt of(S)-2-amino-3-(3,4-diacetoxyphenyl)propionic acid methyl ester (1.5 g,4.5 mmol) was dissolved in dry ethyl acetate and diphosgene (1.1 ml, 9.0mmol) was added while stirring at −10° C. under nitrogen atmosphere.(Care must be exercised in the handling of diphosgene due to release ofphosgene when heated.) The mixture was allowed to warm to roomtemperature, then refluxed for 5 h and evaporated to dryness under highvacuum to give (S)-3-(3,4-diacetoxyphenyl)-2-isocyanatopropionic acidmethyl ester. The isocyanate product was used immediately in the nextreaction without further purification. The product was dissolved in dryacetonitrile (10 ml) with entacapone (553 mg, 1.81 mmol) under nitrogenatmosphere in the absence of light. The mixture was refluxed for 20 hand evaporated to dryness. The product was purified by flashchromatography on silica gel using dichloromethane/methanol (100:1) asan eluent. The acetyl groups were removed by treating with an acetone/3NHCl (20:1) solution for 2 h at 50° C. The resulting clear yellow mixturewas evaporated to dryness and purified by preparative HPLC usingacetonitrile/water (50:50) as an eluent. Evaporation of solvents yielded(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4dihydroxyphenyl)propionicacid methyl ester as a yellow solid (436 mg, 46%), m.p. (decomposed). ¹HNMR (CDCl₃, TMS) δ: 1.26 (6H, br, CH₂CH₃), 2.95 (1H, q, J=6.1 and 13.7Hz, CH_(A)CH), 3.11 (1H, q, J=4.7 and 13.7 Hz, CH_(B)CH), 3.50 (4H, br,CH₂CH₃), 3.77 (3H, s, OCH₃), 4.59 (1H, q, J=5.9 and 7.0 Hz, CH₂CH), 6.14(1H, d, J=7.5 Hz, NH), 6.15 (1H, d, J=8.0 Hz, ArH), 6.66 (1H, s, ArH),6.72 (1H, d, J=8.0 Hz, ArH), 7.52 (1H, s, CH═C), 7.92 (1H, s, J=1.8 Hz,ArH), 8.32 (1H, s, J=1.8 Hz, ArH). ¹³C NMR (CD₃OD) δ: 12.5, 13.6, 37.0,41.1, 43.6, 52.7, 55.4, 107.0, 115.5, 116.6, 121.4, 122.9, 124.9, 127.6,130.0, 134.5, 141.3, 143.3, 143.9, 144.0, 148.1, 151.1, 152.7, 162.9,171.4. ESI-MS: 543.1 (M+1).

EXAMPLE 2(S)—N-{2-[3,4-bis-(2,2-dimethylpropionyloxy)phenyl]-1-(methoxycarbonyl)ethyl}succinamicacid 5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenylester

Levodopa (3.0 g, 15.3 mmol) was mixed with methanol (75 ml) and cooledto 0° C. Thionyl chloride was added during 15 min and the mixture wasstirred at room temperature over night. The solvent was evaporated andthe oily residue was treated with dry diethyl ether. The formed solidmaterial was filtered and dried under vacuum to give the HCl salt of(S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid methyl ester. Yield3.7 g (quant.). The HCl salt of(S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid methyl ester (1.5 g,6.07 mmol) was dissolved in trifluoroacetic acid (10 ml). The mixturewas stirred and cooled to 0° C. and pivaloyl chloride (1.5 g, 12.4 mmol)was added dropwise during 15 min. The mixture was stirred at roomtemperature for 2 h. The solvent was evaporated and the residue wasdissolved in water. The water solution was neutralized with 5% NaHCO₃(aq.) solution and extracted four times with dichloromethane. Thecombined organic layers were dried and evaporated to give(S)-2-amino-3-[3,4-bis-(2,2-dimethylpropionyloxy)phenyl]propionic acidmethyl ester. Yield 2.0 g (87%). A solution of(S)-2-amino-3-[3,4-bis-(2,2-dimethylpropionyloxy)phenyl]propionic acidmethyl ester (1.2 g, 3.2 mmol), succinic acid anhydride (0.38 g, 3.8mmol) and 4-(dimethylamino)pyridine (0.47 g, 3.9 mmol) in ethyl acetate(20 ml) was refluxed for 24 h. After cooling, the reaction mixture waswashed with 1 M citric acid solution (50 ml). The organic layer wasseparated and dried over MgSO₄ and evaporated under vacuum. The residuewas chromatographed over silica using ethyl acetate as an eluent to give(S)—N-{2-[3,4-bis-(2,2-dimethylpropionyloxy)phenyl]-1-(methoxycarbonyl)ethyl}succinamicacid. Yield 1.3 g (86%).(S)—N-{2-[3,4-bis-(2,2-dimethylpropionyloxy)phenyl]-1-(methoxycarbonyl)ethyl}succinamicacid (1.00 g, 2.08 mmol) and entacapone (0.64 g, 2.10 mmol) weredissolved in ethyl acetate (15 ml). Dicyclohexylcarbodiimide (0.51 g,2.47 mmol) and 4-(dimethylamino)pyridine (15 mg) were added and stirringwas continued for24 h. The insoluble material was filtered and thefiltrate was extracted with 5% NaHCO₃ (aq.) solution. The organic layerwas separated, dried, and evaporated. The dark red residue waschromatographed over silica using ethyl acetate as an eluent to give(S)—N-{2-[3,4-bis-(2,2-dimethylpropionyloxy)phenyl]-1-(methoxycarbonyl)ethyl}succinamicacid 5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenylester as a yellow solid. Yield 0.7 g (44%). ¹H NMR ((CD₃)₂CO, TMS) δ:1.22 (6H, s (broad), CH₃CH₂), 1.31 (9H, s, (CH₃)₃C), 1.32 (9H, s,(CH₃)₃C), 2.77 (2H, t, CH₂CH₂), 2.90 (2H, t, CH₂CH₂), 3.05 (1H, dd,CH₂CH), 3.15 (1H, dd, CH₂CH), 3.51 (4H, s (broad), NCH₂CH₃), 3.66 (3H,s, CH₃O), 4.83 (1H, q, CH₂CH), 6.50 (1H, q, NH), 7.05 (1H, d, J⁴=1.8 Hz,ArH), 7.08 (1H, d, J³=8.2 Hz, ArH), 7.12 (1H, dd, J⁴=1.8 Hz, J³=8.2 Hz,ArH), 7.61 (1H, s, CH═C), 7.99 (1H, d, ArH), 8.48 (1H, d, ArH). ¹³C NMR((CD₃)₂CO) δ: 13.39, 27.44, 29.72, 30.86, 37.27, 39.58, 42.77, 52.45,54.38, 106.19, 116.97, 119.72, 124.07, 125.02, 125.25, 126.69, 127.91,136.13, 136.35, 137.79, 142.44, 143.32, 143.88, 147.72, 163.97, 171.23,172.08, 172.78, 176.01, 176.04.

HPLC

The HPLC system used consisted of a Beckman System Gold ProgrammableSolvent Module 126, Beckman System Gold Detector Module 166 withvariable wavelength UV detector (set at 254 nm) and a Beckman SystemGold Autosampler 507e. Separations were accomplished on a PurospherRP-18 reverse-phase column, 12.5 cm×4.0 mm i.d., 5 μm (Merck, Darmstadt,Germany). The chromatographic conditions were as follows: injectionvolume, 50 μl; column temperature, 40° C.; flow rate, gradient/isocraticat 1.0 ml/min. The mobile phase consisted of various proportions ofmethanol/water mixture (90:10) and a citrate/phosphate buffer pH 2.2.

Hydrolysis in Aqueous Solution

The rate of chemical hydrolysis was determined in aqueous phosphatebuffer solution (0.16 M) at pH 7.4, 5.0, and 1.2 at 37° C. Anappropriate amount was dissolved in 10 ml of preheated buffer and thesolution was placed in a thermostatically controlled water bath at 37°C. At appropriate time intervals, samples were taken and analyzed forthe remaining codrug by HPLC. Pseudo-first order half-time (t_(1/2)) forthe hydrolysis was calculated from the slope of the linear portion ofthe plotted logarithm of remaining codrug vs. time.

(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester: t_(1/2)=12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH7.4)

Hydrolysis in 10% Rabbit Liver Homogenate

The rabbit liver was homogenized with approximately four equivalentvolumes of isotonic phosphate buffer at pH 7.4 using an X-1020homogenizer (Ystral, Germany). The homogenate was centrifuged for 90 minat 9,000 g and 4° C. with a Biofuge 28 RS centrifuge (HeraeusInstruments, Germany). The supernatant was stored at −80° C. untilanalysis. An appropriate amount was dissolved in one volume of preheated20% liver homogenate. The solution was then incubated at 37° C. Atappropriate time intervals, samples (300 μl) were withdrawn. Sampleswere pretreated with 300 μl of methanol to terminate enzymatic activity.After mixing and centrifugation, 400 μl of the supernatant wasevaporated to dryness under a stream of air. The residue was dissolvedin 400 μl of the mobile phase buffer and analyzed by HPLC.

(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester: t_(1/2)=7 min (pH 7.4, 37° C.)

1. A compound of general formula I,

wherein E is a COMT inhibitor moiety; G is —(CO)_(a)—, wherein a is 0 or1; T is —(CH₂)_(b)—, wherein b is depending on a if a is 0, then b is 0if a is 1, then b is 2 or 3; R_(d) and R_(e), independently, arehydrogen or a group hydrolyzable under physiological conditions, andsignify optionally substituted lower alkanoyl or aroyl, loweralkanoylamino, optionally substituted lower alkyl or arylsulphonyl oroptionally substituted lower alkylcarbamoyl, or R_(d) and R_(e) takentogether signify a lower alkylidene or cycloalkylidene group; R_(f) ishydrogen or a group hydrolyzable under physiological conditions, andsignifies optionally substituted lower alkanoyl or aroyl, loweralkylamino or lower dialkylamino or lower alkanoylamino, optionallysubstituted lower alkyl or arylsulphonyl, or optionally substitutedlower alkylcarbamoyl; or a pharmaceutically acceptable ester or saltthereof.
 2. A compound according to claim 1, wherein R_(f) is hydrogenor alkyl.
 3. A compound according to claim 1, wherein R_(f) is alkyl. 4.A compound according to claim 1, wherein R_(d) and R_(e), independently,are hydrogen or optionally substituted alkanoyl or aroyl.
 5. A compoundaccording to claim 1, wherein E is a derivative of a catechol compound.6. A compound according to claim 1, wherein E is a moiety of formula Ia,

wherein R₂ is hydrogen, optionally substituted acyl or aroyl, loweralkylsulfonyl or alkylcarbamoyl, X comprises an electronegativesubstituent; R₃ is hydrogen, halogen, substituted alkyl, hydroxyalkyl,amino, nitro, cyano, trifluoromethyl, lower alkylsulfonyl, sulfonamido,aldehyde, alkyl carbonyl, aralkylidene carbonyl or carboxyl or a groupselected from —CH═CR₄R₅ and —CH₂CHR₄R₅, wherein R₄ is hydrogen, alkyl,amino, cyano, carboxyl or acyl; and R₅ is hydrogen, amino, cyano,carboxyl, alkoxycarbonyl, carboxy alkenyl, nitro, acyl, hydroxyalkyl,carboxyalkyl or an optionally substituted carboxamido, carbamoyl oraroyl or heteroaroyl, or R₄ and R₅ together form a five to sevenmembered substituted cycloalkanone ring; —(CO)_(n)(CH₂)_(m)—COR, whereinn is 0 or 1 and m is 0 or 1-7 and R is hydroxy, alkyl, carboxyalkyl,optionally substituted alkene, alkoxy or optionally substituted amino;—CONR₈R₉, wherein R₈ and R₉, independently, are hydrogen or one of thefollowing optionally substituted groups; alkyl, alkenyl, alkynyl,cycloalkyl, or aralkyl, or R₈ and R₉ together form an optionallysubstituted piperidyl group; and —NH—CO—R₁₀, wherein R₁₀ is asubstituted alkyl group.
 7. A compound according to claim 6, wherein R₂is hydrogen.
 8. A compound according to claim 6, wherein X is at anortho position to R₂O—.
 9. A compound according to claim 1, wherein E isa moiety of formula Ib,

wherein R₁ is an electronegative substituent; R₂ is -A-R₄, wherein A isbranched or straight chain (C₁₋₉)alkylene; R₄ is carboxy, 5-tetrazolyl,R₅ or CO—R₅, wherein R₅ is phenyl or (C₃₋₇)cycloalkyl which issubstituted by at least one carboxy or 5-tetrazolyl; and R₃ is anelectronegative substituent.
 10. A compound according to claim 9,wherein R₁ is nitro, cyano, formyl or carboxy.
 11. A compound accordingto claim 9, wherein R₃ is nitro, cyano, halogen, formyl, carboxy,(C₁₋₅)alkylcarbonyl, arylcarbonyl or SO₂R₆, wherein R₆ is a branched orstraight chain (C₁₋₅)alkyl, arylalkyl, aryl or NR₇R₈, wherein R₇ and R₈are, independently, hydrogen or branched or straight chain (C₁₋₅)alkyl,or together form a (C₃₋₆)ring.
 12. A compound according to claim 1,wherein E is a moiety of formula Ic,

wherein R_(a) is nitro or cyano; R_(b) is hydrogen or halogen, R_(c) ishalogen, nitro, cyano or a group -(A)_(n)-(Q)_(m)-R¹ or -(A)_(n)-Q-R²,wherein A is vinylene optionally substituted by lower alkyl, n is 0 or1, m is 0 or 1, R¹ is —COR³, an aromatic carbocyclic group or anaromatic or partially unsaturated heterocyclic group attached via acarbon atom, R² is hydrogen or an optionally substituted, saturated orpartially unsaturated, lower hydrocarbon residue, R³ is hydroxy, amino,an optionally substituted, saturated or partially unsaturated, lowerhydrocarbon residue attached via an oxygen atom or an imino or loweralkylimino group, or a saturated, N-containing, heterocyclic groupattached via a ring nitrogen atom, Q is the group —CO— or>C═N-(Z)_(p)-R⁴, wherein Z is an oxygen atom or an imino group, p is 0or 1 and R⁴ is hydrogen or a saturated or partially unsaturated, lowerhydrocarbon residue, which is optionally substituted and which isoptionally attached via a carbonyl group.
 13. A compound according toclaim 1, wherein E is a moiety of formula Id,

wherein R₂ is hydrogen or a group hydrolyzable under physiologicalconditions, and signifies optionally substituted lower alkanoyl oraroyl, optionally substituted lower alkyl or arylsuiphonyl or optionallysubstituted lower alkylcarbamoyl; R₃, R₄, and R₅ are the same ordifferent and signify hydrogen, optionally substituted saturated orpartially unsaturated lower hydrocarbon residue, hydroxy, an optionallysubstituted lower alkoxy or aryloxy group, optionally substituted aryl,an optionally substituted alkanoyl or aroyl group, a lower alkanoylaminogroup, a lower dialkanoylamino group, carboxyl, an optionallysubstituted lower alkyloxycarbonyl or aryloxycarbonyl group, optionallysubstituted carbamoyl, halogen, nitro, amino, lower alkylamino or lowerdialkylamino or cyano group, or R₃, R₄, and R₅ taken together signifyaliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings.14. A compound according to claim 13, wherein R₂ is hydrogen. 15.(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester, or a pharmaceutically acceptable ester or saltthereof. 16.(S)-3-(3,4-dihydroxyphenyl)-2-[2-hydroxy-5-(4-methylbenzoyl)-3-nitrophenoxycarbonylamino]propionicacid methyl ester, or a pharmaceutically acceptable ester or saltthereof. 17-19. (Canceled)
 20. A pharmaceutical composition comprising acompound as claimed in claim 1,

and further comprising a pharmaceutically acceptable excipient.
 21. Apharmaceutical composition according to claim 20, wherein the compoundis(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester, or a pharmaceutically acceptable ester or saltthereof.
 22. A pharmaceutical composition according to claim 20, whereinthe compound is(S)-3-(3,4-dihydroxyphenyl)-2-[2-hydroxy-5-(4-methylbenzoyl)-3-nitrophenoxycarbonylamino]propionicacid methyl ester, or a pharmaceutically acceptable ester or saltthereof.
 23. A method for the treatment of diseases or conditions,wherein levodopa and inhibition of COMT are indicated to be useful, saidmethod comprising administering to a mammal in need of such treatment aneffective amount of a compound as claimed in claim 1,


24. A method according to claim 23, wherein the compound is(S)-2-{5-[(E)-2-cyano-2-(diethylcarbamoyl)vinyl]-2-hydroxy-3-nitrophenoxycarbonylamino}-3-(3,4-dihydroxyphenyl)propionicacid methyl ester, or a pharmaceutically acceptable ester or saltthereof.
 25. A method according to claim 23, wherein the compound is(S)-3-(3,4-dihydroxyphenyl)-2-[2-hydroxy-5-(4-methylbenzoyl)-3-nitrophenoxycarbonylaminol]propionicacid methyl ester, or a pharmaceutically acceptable ester or saltthereof.
 26. A compound according to claim 6, wherein X compriseshalogen, nitro, cyano, lower alkylsulfonyl, sulfonamido, aldehyde,carboxyl, or trifluoromethyl.